Remarkable genetic differences in the alcohol-metabolizing enzymes, i.e., alcohol dehydrogenase and aldehyde dehydrogenase, have been recognized between Caucasians and Orientals. It has been suggested that the very high incidence of alcohol sensitivity in Orientals could be due to the rapid acetaldehyde formation by the Oriental-type alcohol dehydrogenase variant (ADH-2-2) with high catalytic activity, or due to the accumulation of acetaldehyde caused by the absence of one of the major aldehyde dehydrogenase isoenzymes (ALDH2, mitochondrial isozyme) in the majority of Orientals. A lower incidence of alcoholism in Orientals than in Caucasians could be due to most alcohol-sensitive subjects being discouraged from drinking heavily. Utilizing the cDNA clones for human ADHs and ALDHs, which were obtained under the present grant, the following projects will be undertaken: 1) Study of the genomic organization of three major ADH (i.e., ADH-1, ADH-2, ADH-3) loci; 2) Study of the genomic structures of ALDH-1 (for cytosolic isozyme) and ALDH-2 (for mitochondrial isozyme) loci; 3) Study of restriction-site polymorphism related to these gene loci; and 4) Determination of genotype distributions of these loci in Caucasians, Orientals, and American Indians, and in alcohol-sensitive and alcoholic subjects. These studies will extend our knowledge of the genomic structures of the human ADH gene cluster and the ALDH-1 and ALDH-2 loci, and shed light on the process of evolutional divergence of these isozymes. The possible correlation between the genetic background (i.e., genotypes of these genes and restriction-site polymorphism associated with these loci) and the predisposition of alcohol sensitivity and/or alcoholism will be clarified.